Multilayered articles having biocompatibility and biostability characteristics

ABSTRACT

Multilayer articles, such as tubing and films, are disclosed which have a soft layer of aliphatic polyurethane and at least one layer of hard aliphatic polyurethane. The articles formed avoid the problem of tackiness when using only a soft aliphatic polyurethane, while maintaining flexibility. The articles are also biocompatible and biostable and are suitable for use in medical applications.

CROSS-REFERENCE

This patent application is a division of U.S. Pat. No. 7,264,858 issuedon Sep. 4, 2007, which claims priority to Provisional Application Ser.No. 60/422,032 filed on Oct. 29, 2002.

BACKGROUND OF THE INVENTION

Polyvinylchloride (PVC) is an accepted material for use as tubing invarious medical applications and is commonly used as tubing in foodprocessing, particularly for fluids and semi-solids. PVC polymer chainsform an attraction to one another, which produces a very rigid plastic.When a soft or flexible plastic is required, a plasticizer may be addedto allow the chains to slide against each other. Phthalates may be usedas a plasticizer for PVC medical and surgical products, such as a IVtubes, blood bags, and ventilation tubes.

It is believed that phthalate does not bind to the PVC, remainingpresent as a freely mobile and leachable phase in the plastic. It isalso believed that phthalates migrate out of the PVC polymer, since itis not bound to the PVC molecule. When used in medical tubing, phthalatehas been found to accumulate in blood, lung, and liver tissue, as wellas in fat. These plasticizers may have ill effects on humans, and inparticular, children.

SUMMARY OF THE INVENTION

The invention includes a multilayered article comprising a first layerof soft polyurethane having an inner and outer surface and at least onesecond layer of hard polyurethane on at least one of the inner and outersurface. The soft and hard polyurethanes are aliphatic polyurethanes andare polyether or polycarbonate based, that is, the polyol used toproduce the polyurethane is either a polyether or polycarbonate. Thepolyurethanes used in this invention are biocompatible and biostable andthus the articles made are suitable for medical applications.

The invention also involves a process for producing the articles bycoextrusion or solution casting.

BRIEF DESCRIPTION OF THE DRAWINGS

The accompanying drawings, which are incorporated herein and constitutea part of this specification, illustrate the presently preferredembodiments of the invention and, together with the general descriptiongiven above and the detailed description given below, serve to explainthe features of the invention. The drawings are not shown to scale.

In the drawings:

FIG. 1 is a diagram of a process for making an embodiment of theinvention;

FIG. 2 is a cross-sectional view of a first embodiment of the inventionshowing a tube with an inner layer of soft polyurethane and an outerlayer of hard polyurethane;

FIG. 3 is a cross-sectional view of a second embodiment of the inventionshowing a tube with an outer layer and inner layer of hard polyurethanewith a layer of soft polyurethane between the two hard layers;

FIG. 4 is a cross-sectional view of a third embodiment of the inventionshowing a tube with an inner layer of hard polyurethane and an outerlayer of soft polyurethane; and

FIG. 5 is a cross-sectional view of a fourth embodiment of the inventionshowing a profile tube having an outer layer of hard polyurethane and aninner layer of soft polyurethane.

DESCRIPTION OF THE INVENTION

The present invention is directed to a coating of a hard material on thesurface of a soft material. The product, which is preferably, tubing orfilm, a multilayered article that has soft characteristics forflexibility, patient comfort and ease of clamping to control the flow offluids. For medical grade tubing, the product preferably has goodbonding properties and minimizes risk of exposing a patient tosubstances that can migrate from the tubing to medical fluids, such asblood, saliva, etc.

In one embodiment, the hard material, or coating, and soft material arepolymers that are characterized as essentially linear, segmented,aliphatic polyurethane elastomers. This family of polymers, beingaliphatic and polyether or polycarbonate-based with 100% urethanelinkages in the molecular backbone, exhibit superior flexural life andoutstanding hydrolytic stability. In addition, the polymers can bepelletized and extruded to form a variety of shaped devices.

In one embodiment, the soft material is a soft/tacky polyurethane. Softgrades of polyurethane alone are tacky. Tacky materials are difficult tohandle and they stick together and to other materials, such aspackaging. Tacky materials are difficult to separate, especially whenclamped, and are difficult to move passed each other and passed othermaterials. When the tacky materials are warm, the tack points createoptical defects. These defects may effect the performance of theproduct. However, with a hard material, such as polyurethane coating,placed on the soft material, such as polyurethane, the problemsassociated with tacky materials diminish.

Basic polyurethanes are reaction products of at least one polyol, whichcan be a polyether, polycarbonate or polyester, with a diisocyanate orpolyfunctional isocyanate material. Typically, a polyurethane has threebasic building blocks: a polyol, a diisocyanate and a chain extender.Polyurethane polymers contain hard segments and soft segments, whichgives it rubbery properties. The soft segment is made up of the polyol,while the hard segment is made up from the diisocyanate and the chainextender. The hardness of the polyurethane can be adjusted by the amountof the reactants used to make the polyurethane. Greater amounts ofpolyol will give softer materials while greater amounts of diisocyanateand chain extender give harder materials. The polyol used in thisinvention is preferably a polycarbonate glycol, such as polycarbonatediol or a polyether diol.

Hydroxyl terminated polycarbonates can also be used as the polyol forthe polyurethanes of this invention. Molecular weight (Mn) of thepolycarbonate polyol can vary from about 500 to about 10,000 but in apreferred embodiment, it will be in the range of about 500 to about2,500. When polycarbonate is used as the polyol, the resultingpolyurethane is referred to as a polycarbonate polyurethane. Thehydroxyl terminated polycarbonate polyol can be prepared by reacting aglycol with a carbonate. U.S. Pat. No. 4,131,731 discloses hydroxylterminated polycarbonates and their preparation.

Hydroxyl terminated polyether polyols are derived from a diol or polyolhaving a total of from 2 to 15 carbon atoms, preferably an alkyl diol orglycol which is reacted with an ether comprising an alkylene oxidehaving from 2 to 6 carbon atoms, typically ethylene oxide or propyleneoxide or mixtures thereof. For example, hydroxyl functional polyethercan be produced by first reacting propylene glycol with propylene oxidefollowed by subsequent reaction with ethylene oxide. Primary hydroxylgroups resulting from ethylene oxide are more reactive than secondaryhydroxyl groups and thus are preferred. Useful commercial polyetherpolyols include poly(ethylene glycol) comprising ethylene oxide reactedwith ethylene glycol, poly(propylene glycol) comprising propylene oxidereacted with propylene glycol, poly(tetramethyl glycol) comprising waterreacted with tetrahydrofuran (PTMG). Polytetramethylene ether glycol(PTMEG) is the preferred polyether polyol. Polyether polyols furtherinclude polyamide adducts of an alkylene oxide and can include, forexample, ethylenediamine adduct comprising the reaction product ofethylenediamine and propylene oxide, diethylenetriamine adductcomprising the reaction product of diethylenetriamine with propyleneoxide, and similar polyamide type polyether polyols. Copolyethers canalso be utilized in the current invention. Typical copolyethers includethe reaction product of THF and ethylene oxide or THF and propyleneoxide. These are available from BASF as Poly THF B, a block copolymer,and poly THF R, a random copolymer. The various polyether polyolsgenerally have a number average molecular weight (Mn), as determined byassay of the terminal functional groups which is an average molecularweight, of from about 500 to about 10,000, desirably from about 500 toabout 5,000, and preferably from about 700 to about 3,000.

The diisocyanate is an isocyanate compound with the functionality of twoisocyanates. Exemplary aliphatic diisocyanates include hexamethylenediisocyanate (HDI), isophorone diisocyanate (IPDI), trimethylhexamethylene diisocyanate (TMHDI), dicyclohexyl methane diisocyanate(HMDI), and dimer acid diisocyanate (DDI). The diisocyanate ispreferably HMDI.

Suitable chain extenders are lower aliphatic or short chain glycolshaving from about 2 to about 10 carbon atoms and include for instanceethylene glycol, diethylene glycol, propylene glycol, dipropyleneglycol, 1,4-butanediol, 1,6-hexanediol, 1,3-butanediol, 1,5-pentanediol,1,4-cyclohexanedimethanol hydroquinone di(hydroxyethyl)ether,neopentylglycol, and the like. The preferred chain extender is1,4-butanediol. The mechanical properties of the polyurethane tend tochange with changes in molecular weight, intermolecular forces, andbuilding blocks of the polyurethane. The ratio of polyol to diisocyanategenerally determines the hardness of the polyurethane. Preferably, thesoft and tacky polyurethanes have a Shore durometer of from about 40A toabout 95A, preferably from about 65A to about 85A, and the hardpolyurethanes have a Shore durometer of from about 95A to about 85D,preferably from about 40D to about 75D. The durometers are determined byASTM D2240. If a polycarbonate aliphatic polyurethane is used as thehard layer, a slightly lower Shore hardness may be used than when apolyether aliphatic polyurethane is used. When a polycarbonate aliphaticpolyurethane is used as the hard layer, the Shore hardness of the hardlayer will be from about 70A to about 80D, preferably from about 95A toabout 60D. Polycarbonate polyurethanes are not as tacky as polyetherpolyurethanes and therefore less hardness is required in thepolycarbonate polyurethane to remove the tack problem.

Other chemical, mechanical, and biological properties of the softmaterial and the hard material include high tensile strength, highultimate elongation, good biocompatibility, high abrasion resistance,good hydrolytic stability, capability of sterilization with ethyleneoxide and gamma radiation, retention of elastomeric properties at lowtemperature, and good melt processing characteristics for extrusion,injection molding, and other processes. Exemplary polyurethanes includethermoplastic polyurethanes, available from Thermedics Polymer Productsand commercially available as Tecoflex® polyurethanes, Tecothane®polyurethanes, and Carbothene® polyurethanes. Other ingredients may beadded to the polyurethane polymers used in this invention. Such otheringredients can include catalysts, antioxidants, lubricants, tintingagents, and the like as are well known to those skilled in the art.Preferably, the other ingredients are added to the reactants before thereaction occurs to form the polyurethane.

The polyurethanes may be synthesized to range from very hard to soft totacky. The polyurethanes may be manufactured by reacting a hydroxylgroup of the polyol, or polycarbonate glycol, with an isocyanate groupof the diisocyanate component and the other isocyanate group of thediisocyanate with a terminal hydroxyl or amine group of the chainextender. In one embodiment, the polymerization is carried out in thepresence of a solvent. In another preferred embodiment, thepolymerization involves a bulk polymerization process. In the bulkpolymerization process, all of the raw materials are melted and placedin a reactor, where the reaction is initiated with the addition ofisocyanate. The polymerization takes place in the presence of adifunctional hydroxyl compound.

For example, as shown in FIG. 1, the polyurethane may be prepared fromtwo components, which can be referred to as part A and part B. Part A isthe aliphatic diisocyanate. Part B is comprised of the polyol, theglycol chain extender, a catalyst, an antioxidant, and a lubricant. Theproper stoichiometric proportions of part A and part B are emulsified bya mixer at room temperature to form a moderately reactive thixotropicmixture having a viscosity below about 2500 cps. Since theemulsification introduces air into the reactive mixture, the air must beremoved. The air bubbles are removed by placing a vessel containing theemulsion under a bell jar and evacuating the air from the bell jar witha suction device. The bell jar is evacuated to a pressure of about 0.3microns and the mixture is kept under the bell jar about 8 minutescausing the mixture to appear to boil. After the emulsion is taken fromthe bell jar, it is allowed to stand until the exothermic reaction thatis taking place brings it to a temperature of about 40° C.

At this point, the emulsion is preferably poured into a pan where it isallowed to flow to form uncured sheets. The pan with the sheets is thenplaced in an oven and heated at a temperature of at least 110° C. forfour hours or more until the elastomer is cured. The sheets are thenchopped up or pelletized in a standard pelletizer resulting in pelletsapproximately ¼ inch in length. These pellets are then used in machinerysuitable for an extrusion of the desired product. Alternatively, thepellets may be dissolved in a solvent, such as dimethyl acetamide,tetrahydrofuran, 1,4 dioxane and m-pyrrol. The solution may then be usedto make an article by a solvent casting method. These methods arefurther described in U.S. Pat. No. 4,447,590, the entire content ofwhich is hereby incorporated by reference.

The hard material (e.g., polyurethane) coating decreases tubing chemicalsusceptibility (solvent attack), cosmetic defects found with the softextruded materials, and tack found with the soft material. The coatingof hard material (e.g., polyurethane) improves the strength of the tube,decreases drug interactions with the tube, and improves biocompatibilityof the tube surfaces. The coating also allows the use of soft/tackymaterial (e.g., polyurethane) without any additives that would reducethe tack through chemistry.

In particular, at least the fluid contacting surfaces of the tubingcontain no phthalate or citrate esters or other plasticizers, which arecapable of leaching into pharmaceutical fluids. Blood clotting,rejection responses, and tissue inflammation are minimized. Thepolymeric blends, tubing, and tubing assemblies also preferably avoidabsorption of solvents, drugs, pharmaceutical agents and other materialsthat come in contact with them. The polyurethanes of this invention passbiocompatibility and biostability testing.

To demonstrate the biocompatibility of the aliphatic polyurethanes usedin this invention, the following tests are used:

Test Procedure Minimum Essential ISO 10993 - Part 5, (1999); Tests forin vitro Medium (MEM) Elution cytotoxicity Indirect Hemolysis ISO10993 - Part 4, (1992); Selection of tests for interactions with bloodIn Vitro ISO 10993 - Part 4, (1992); Selection of testsHemocompatibility for interactions with blood Systemic Injection StudyISO 10993 - Part 11 (1993); Tests for systemic toxicity; Extractionprocedures were based on ISO Standard 10993-12 (1996) Intracutaneous ISO10993 - Part 10 (1995); Tests for irritation and sensitization tests;Extraction procedures were based on ISO Standard 10993-12 (1996) PyrogenISO 10993 - Part 11, (1993); Tests for systemic toxicity; Extractionprocedures were based on ISO Standard 10993-12. (1996) PhysiochemicalTest for United States Pharmacopoeia 24, National Plastics Formulary 19,pp. 1932-1933, 2000.

To demonstrate the biostability of the aliphatic polyurethanes used inthis invention, the test used was the Implantation test, 2-weekhistopathology. The test was conducted in accordance with ISO Standards10993—Part 6 (1994); tests for local effects after implantation.

The hard and soft layers of the articles made according to thisinvention both pass all of the above listed tests for biocompatibilityand biostability. This is an important feature of this invention. Sincethe end use products, such as tubing, of this invention are to be usedin medical applications, it is important that they exhibitbiocompatibility and biostability.

The hard material (e.g., polyurethane) can be placed on the outersurface, the inner surface or both surfaces of the soft material (e.g.,polyurethane). For example, FIG. 2 shows a device, such as medicaltubing, having a hard material 10 on an outer surface 12 of a softmaterial 14, FIG. 3 shows coatings 20 and 21 placed on an outer surface22 and inner surface 23, respectively, of a soft polyurethane 24. Theinner and outer hard coating materials may be the same materials,similar materials, or different materials. FIG. 4 shows a hard coating31 placed on an inner surface 33 of a soft polyurethane 34. AlthoughFIGS. 2-4 show the coatings on a round device, the device may be of anyshape and size. For example, the tubing may be a profile tube, as shownin FIG. 5, where a coating 40 is placed on an outer surface 42 of a softpolyurethane 44.

In addition, the hard materials may be placed on other medical devices,as well as non-medical devices that contain tacky materials. Forexample, the hard material may be placed on piping used as process linesin aqueous systems, such as water treatment systems, potable andnon-potable water supply lines, low pressure feed lines, exhaust lines,water or aqueous discharge lines, gas vents, conduit for dry solids,underground conduit for wiring, and overhead conduit and on piping usedin secondary containment systems, sewer lining systems, irrigationsystems, production wells, monitoring wells, injection wells, leachatecollection systems, and sprinkler systems. The coating may also be usedon sheeting, including stockpile covers (e.g., cover contaminated soilsto prevent rainwater from infiltrating soils and groundwater), pond,container, and lagoon liners, truck bed liners, dump truck covers,foundation liners, boots for sealing piping with other structures,barriers in slurry walls, and dust control enclosures and grids andmesh, including geo-grids for soil stabilization, temporary fencing,sacrificial layer in underground utilities, wick drains, filterapplications such as in soil collection systems, and silt fence. Furtherapplications include drums, lids, and other containers, temporary damstructures, concrete form for underwater applications, pontoons andother buoyancy devices, and disposable boots and boot liners, gloves,and sampling devices.

The hard material improves handling of the article and is placed on thearticle in a thickness not to effect the soft characteristics of thearticle. The thickness of the coating must be large enough to reduce thesurface tack, but small enough to not significantly change the stiffnessof the article. In one embodiment, the thickness of the coating rangesfrom about 0.0001 to 0.010 inches, depending on the size of the tube.For example, for a tube with a 0.025 inch wall, the preferred coatingthickness is about 0.0005 to 0.001 inches. For larger tubes, thethickness of the hard material could be thicker than 0.001 inches.

In one embodiment, processing of the materials is performed under commoncoextrusion techniques. Coextrusion is a polymer processing method forbringing different polymeric materials together to form unitary layeredstructures, such as films, sheets, fibers, and tubing. This allows forunique combinations of materials, and for structures with multiplefunctions, such as, barrier characteristics, radiation resistance, andheat sealability. In coextrusion processes, different extruders are usedfor each different material used in making the desired article. Forexample, if two materials are used, such as a soft and hardpolyurethane, two extruders would be used. The melt streams are broughttogether to form the coextruded final article. The materials are broughttogether hot in the coextrusion process and are melt bonded together. Ifthree materials are used, then three extruders would be used, and soforth. The shape and/or thickness of the coextruded layers depends uponthe efficiency of the particular extrusion equipment utilized.Coextrusion may also be combined with blown film processing so that filmstructures can be made with no inherent waste and much lower capitalinvestment over flat film coextrusion. However, flat film processingtechniques provide an excellent method for making multilayeredstructures. Film made according to this invention can be fabricated intocontainers, such as blood and IV bags by heat sealing the film.

Component polymer or copolymer materials according to the presentinvention can be coextruded from the melt state in any shape, which israpidly cooled to obtain a multilayered structure. The shape and/orthickness of the coextruded structure will be dependent upon theefficiency of the particular extrusion equipment employed and thequenching systems utilized. Generally, films and tubes are the preferredcoextruded structures.

The components are thoroughly mixed prior to being charged to theextruder (e.g., pellets of the individual materials are blended togetherprior to being charged into the extruder where they are further mixed bythe extruder and extruded). Alternatively, the materials may beindividually metered into the extruder in the correct proportion. Thepellets should be dried to a moisture content of 0.05% or less prior toextruding.

In one embodiment, once the tubing has been extruded in appropriatelengths and sizes, tubing assemblies may be formed by bonding theselengths to one or more plastic fluid transporting components. Fortubing, the sizes may range from about 0.003 inch inner diameter(ID)×about 0.011 inch outer diameter (OD) to about 0.500 inch ID×about0.550 inch OD. Preferably, the OD ranges from about 0.06 inches to about0.2 inches with a wall thickness of about 0.01 to 0.03 inches. Thelength may be about 0.125 inches or longer.

The preferred dies used to manufacture coextruded tubing are generallycommercially available, i.e., Genca in Clearwater, Fla. However, anyavailable dies may be used. The standard extrusion conditions for thematerials of interest will work for this application.

REPRESENTATIVE EXAMPLE

To co-extrude a tube as shown in FIG. 2, the soft layer 14 is analiphatic polyurethane having a Shore Hardness of 80A and the hard layer10 is an aliphatic polyurethane having a Shore Hardness of 60D. Both thesoft and hard polyurethanes are extrusion grade and are commerciallyavailable as Tecoflex® from Thermedics Polymer Products in Wilmington,Mass., U.S.A. Prior to extruding, the pellets of the soft and hardpolyurethanes are dried to a moisture content of 0.05% or less. Twoextruders are used, a 1 inch extruder for the hard layer and a 1½ inchextruder for the soft layer. Each extruder has 4 heat zones. Theextruder heat zone temperatures and conditions for the soft layer is asfollows:

Zone 1 - 330° F. ± 25° F. Zone 2 - 340° F. ± 25° F. Zone 3 - 350° F. ±25° F. Zone 4 - 360° F. ± 25° F. Melt Temp. - 360° F. ± 25° F. DieTemp. - 360° F. ± 25° F. Pressure - 1,000-2,500 psi Screen Pack - 500meshThe extruder heat zone temperatures and conditions for the hard layer isas follows:

Zone 1 - 360° F. ± 25° F. Zone 2 - 370° F. ± 25° F. Zone 3 - 380° F. ±25° F. Zone 4 - 390° F. ± 25° F. Melt Temp. - 390° F. ± 25° F. DieTemp. - 390° F. ± 25° F. Pressure - 2,000-4,000 psi Screen Pack - 500mesh

The pellets of the soft and hard polyurethane layers are fed to theirrespective extruder and coextruded into a tube shape using acommercially available die from Genca in Clearwater, Fla., U.S.A. Thecoextruded tube is cooled and wound into a roll.

If harder of softer materials are used for the two layers, therecommended extrusion temperatures will need to be adjusted, as is wellknown to those skilled in the art of extrusion. Usually, for a harderpolyurethane, the extrusion temperature is adjusted higher and for asofter polyurethane, the extrusion temperature is adjusted lower.

The individual layers of the tube pass biocompatibility and biostabilitytesting.

In addition, coating could be added by common solution cast methods. Inone example of a common solution cast method, 10 grams of hardpolyurethane are dissolved in 500 grams of tetrahydrofuran. Dimethylacetamide, cyclohexanone, cyclopentanone, dimethyl formamide, methylenechloride, or dioxane may also be used. The solution is placed into adipping tank and the tubing is attached to an apparatus to dip thetubing. At a controlled rate (for example, 20 inches/minutes), the tubeis dipped into the solution and retracted. The excess solvent is allowedto drip off the tube and the solvent is evaporated.

Tubing and tubing assemblies according to the present invention can beutilized in a wide range of both medical and non-medical products. Inthe medical area, the tubing and tubing assemblies are suitable forreplacing chlorine-containing PVC tubing, such as is utilized with IVfluid administration sets, infusion sets, cassettes, arthroscopy fluidcontrol systems, cardiovascular systems and blood gas monitoringsystems.

While the invention has been described in detail and with reference tospecific embodiments thereof, it will be apparent to one skilled in theart that various changes and modifications can be made therein withoutdeparting from the spirit and scope thereof. Thus, it is intended thatthe present invention covers the modifications and variations of thisinvention provided they come within the scope of the appended claims andtheir equivalents.

1. A process for making a multilayer tube comprising: providing a hardaliphatic polyurethane selected from the group consisting of polyetherpolyurethane and polycarbonate polyurethane having a Shore hardness fromabout 95A to about 85D as measured according to ASTM D2240, with theproviso that if said aliphatic polyurethane is a polycarbonatepolyurethane, said Shore hardness of said hard aliphatic polyurethane isfrom about 70A to about 80D, and a soft aliphatic polyether polyurethanehaving a Shore hardness from about 40A to about 95A as measuredaccording to ASTM D2240; coextruding said soft aliphatic polyurethaneand said hard aliphatic polyurethane to form a multilayer tube; whereinboth of said soft aliphatic polyurethane and said hard aliphaticpolyurethane are biocompatible and biostable.
 2. The process of claim 1,wherein said hard aliphatic polyurethane has a Shore hardness of fromabout 40D to about 75D, and wherein said soft aliphatic polyurethane hasa Shore hardness of from about 65A to about 85A.
 3. The process of claim1, wherein said tube has a thickness of said hard aliphatic polyurethaneof from about 0.0005 to about 0.001 inch.